Meeseon Jeong

Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of AKT and MDM2.

Ret finger protein 2 (RFP2), a gene frequently deleted in multiple tumor types, encodes a protein with a RING finger, B-box, and coiled-coil domain that belongs to the RBCC/TRIM protein family. Although RBCC proteins are involved in diverse cellular processes such as apoptosis, proliferation, differentiation, and transcriptional regulation, the biological function of RFP2 has not been well defined. Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. The expression of RFP2, which possesses RING domain-dependent E3 ubiquitin ligase activity, was increased by ionizing radiation dose- and time-dependently, and RFP2 overexpression induced cell death with increased expression of apoptotic molecules (p53, p21, and Bax). These results depended on the E3 ubiquitin ligase activity of RFP2 because mutant RFP2, which contains a mutated RING domain, failed to drive apoptosis compared with wild-type RFP2. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. Thus, these data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation.

Phosphorylation of CLK2 at Serine 34 and Threonine 127 by AKT Controls Cell Survival after Ionizing Radiation

AKT phosphorylates components of the intrinsic cell survival machinery and promotes survival to various stimuli. In the present study, we identified CDC-like kinase 2 (CLK2) as a new substrate of AKT activation and elucidated its role in cell survival to ionizing radiation. AKT directly binds to and phosphorylates CLK2 on serine 34 and threonine 127, in vitro and in vivo. CLK2 phosphorylation was detected in HeLa cells overexpressing active AKT. In addition, we demonstrated that ionizing radiation induces CLK2 phosphorylation via AKT activation. In contrast, the suppression of endogenous AKT expression by siRNA inhibited CLK2 phosphorylation in response to 2 gray of γ-ray or insulin. Furthermore, we examined the effect of CLK2 on the survival of irradiated CCD-18Lu cells overexpressing Myc-CLK2. CLK2 overexpression significantly increased cell growth and inhibited cell death induced by 2 gray. The role of CLK2 in cell survival to ionizing radiation was dependent on the phosphorylation of serine 34 and threonine 127. Our results suggest that AKT activation controls cell survival to ionizing radiation by phosphorylating CLK2, revealing an important regulatory mechanism required for promoting cell survival.

A critical role for AKT activation in protecting cells from ionizing radiation-induced apoptosis and the regulation of acinus gene expression

Although AKT activation leads to the activation of various pathways related to cell survival, the roles of AKT in modulating cellular responses induced by ionizing radiation in normal human cells remain unclear. Here we show that low-dose radiation of 0.05Gy did not affect cell death, but high-dose radiation (> 0.2Gy) induced apoptosis through the activation of caspases and acinus cleavage. Ionizing radiation induced acinus phosphorylation via AKT activation. Thus, we examined the effect of AKT activation on radiation-induced cell death using CCD-18Lu cells transduced with a retroviral vector expressing constitutively active AKT (CA-AKT). The overexpression of CA-AKT rendered the cells resistant to ionizing radiation and prevented the proteolytic cleavage of acinus via phosphorylation. In addition, overexpression of CA-AKT resulted in the upregulation of acinus expression by activation of the NF-kappaB pathway. On the other hand, suppression of endogenous AKT expression by siRNA resulted in the reduction of acinus expression and enhanced the radiation-induced apoptosis in both CCD-18Lu and IM-9 cells. Our results suggest that AKT activation inhibits cell death during radiation-induced apoptosis through the regulation of phosphorylation and expression of acinus. The AKT/NF-kappaB/acinus pathway functions as one of the important regulatory mechanisms required for modulating ionizing radiation sensitivity.

Cancer Risk in Diagnostic Radiation Workers in Korea from 1996-2002

This study was aimed to examine the association between the effective radiation dose of diagnostic radiation workers in Korea and their risk for cancer. A total of 36,394 diagnostic radiation workers (159,189 person-years) were included in this study; the effective dose and cancer incidence were analyzed between the period 1996 and 2002. Median (range) follow-up time was 5.5 (0.04–7) years in males and 3.75 (0.04–7) years in females. Cancer risk related to the average annual effective dose and exposure to more than 5 mSv of annual radiation dose were calculated by the Cox proportional hazard model adjusted for occupation and age at the last follow-up. The standardized incidence ratio of cancer in radiation workers showed strong healthy worker effects in both male and female workers. The relative risk of all cancers from exposure of the average annual effective dose in the highest quartile (upper 75% or more of radiation dose) was 2.14 in male workers (95% CI: 1.48–3.10, p-trend: <0.0001) and 4.43 in female workers (95% CI: 2.17–9.04, p-trend: <0.0001), compared to those in the lower three quartiles of radiation exposure dose (less than upper 75% of radiation dose). Cancer risks of the brain (HR: 17.38, 95% CI: 1.05–287.8, p-trend: 0.04) and thyroid (HR: 3.88, 95% CI: 1.09–13.75, p-trend: 0.01) in female workers were significantly higher in the highest quartile group of radiation exposure compared to those in the lower three quartiles, and the risk of colon and rectum cancers in male workers showed a significantly increasing trend according to the increase of the average annual radiation dose (HR: 2.37, 95% CI: 0.99–5.67, p-trend: 0.02). The relative risk of leukemia in male workers and that of brain cancer in female workers were significantly higher in the group of people who had been exposed to more than 5 mSv/year than those exposed to less than 5 mSv/year (HR: 11.75, 95% CI: 1.08–128.20; HR: 63.11, 95% CI: 3.70–1,075.00, respectively). Although the present study involved a relatively young population and a short follow-up time, statistically significant increased risks of some cancers in radiation workers were found, which warrants a longer follow-up study and more intensive protective measures in this population.

Ionizing Radiation-induced Diseases in Korea

Radiation risk has become well known through epidemiological studies of clinically or occupationally exposed populations, animal experiments, and in vitro studies; however, the study of radiation related or induced disease has been limited in Korea. This study is to find the level of occupational radiation exposure for various kinds of accidents, compensated occupational diseases, related studies, and estimations on future occupational disease risks. Research data of related institutions were additionally investigated. About 67% of 62,553 radiation workers had no exposure or less than 1.2 mSv per year. The 5 reported cases on radiation accident patients in Korea occurred during nondestructive testing. According to the recent rapid increase in the number of workers exposed to radiation, a higher social recognition of cancer, and an increasing cancer mortality rate, it is expected that occupational disease compensation will rapidly increase as well. Therefore, it is important to develop scientific and objective decision methods, such as probability of causation and screening dose in the establishment of an exposure and health surveillance system.

Health Effects of the Chernobyl Accident

The Chernobyl accident was a terrible catastrophe for humanity. Scientists are in concurrence about an increase of thyroid cancer incidence among children, but not among adults, because even areas less contaminated by radiation have also reported an increase in the incidence of thyroid cancer. In this case, the rise might be due to a screening effect. There is no convincing evidence that the incidence of leukemia and solid cancer has increased among the exposed populations, but it still remains a controversial issue. Additionally, apparent evidence of decreased fertility and increased hereditary effects have not been observed in the general population. WHO suggested 4,000 people could have died or may die in the future among emergency workers and residents of the most contaminated areas, while Greenpeace insists there will be 93,080 victims around the world. The radiation dose due to Chernobyl was mainly low, so if its health effects are to be found, more long-term and welldesigned research will be needed.The Chernobyl accident was a terrible catastrophe for humanity. Scientists are in concurrence about an increase of thyroid cancer incidence among children, but not among adults, because even areas less contaminated by radiation have also reported an increase in the incidence of thyroid cancer. In this case, the rise might be due to a screening effect. There is no convincing evidence that the incidence of leukemia and solid cancer has increased among the exposed populations, but it still remains a controversial issue. Additionally, apparent evidence of decreased fertility and increased hereditary effects have not been observed in the general population. WHO suggested 4,000 people could have died or may die in the future among emergency workers and residents of the most contaminated areas, while Greenpeace insists there will be 93,080 victims around the world. The radiation dose due to Chernobyl was mainly low, so if its health effects are to be found, more long-term and welldesigned research will be needed.

A national survey of occupational radiation exposure among diagnostic radiologic technologists in South Korea

The objective of this study was to investigate representative occupational characteristics and radiation exposure for South Korean radiologic technologists. The authors conducted a national survey by stratified sampling of South Korean administrative districts and types of medical facilities. A total of 585 technologists were surveyed, and survey data were linked with dosimetry data from the National Dose Registry. A total of 73 % of radiologic technologists sampled were male, 62 % were younger than age 40 and 86.5 % began employment after 1990. The most frequent practices among radiologic technologists were diagnostic routine X-ray followed by computed tomography (CT) and portable X-ray. Male workers were more frequently involved in CT, portable X-ray and interventional radiology whereas female workers carried out most mammography procedures. The average annual effective dose was 2.3 mSv for male and 1.3 mSv for female workers. The dose was significantly higher for workers in the provinces and those who had recently started work.

Probability of causation for occupational cancer after exposure to ionizing radiation

BackgroundProbability of causation (PC) is a reasonable way to estimate causal relationships in radiation-related cancer. This study reviewed the international trend, usage, and critiques of the PC method. Because it has been used in Korea, it is important to check the present status and estimation of PC in radiation-related cancers in Korea.MethodsResearch articles and official reports regarding PC of radiation-related cancer and published from the 1980s onwards were reviewed, including studies used for the revision of the Korean PC program. PC has been calculated for compensation-related cases in Korea since 2005.ResultsThe United States National Institutes of Health first estimated the PC in 1985. Among the 106 occupational diseases listed in the International Labor Organization Recommendation 194 (International Labor Office (ILO), ILO List of Occupational Diseases, 2010), PC is available only for occupational cancer after ionizing radiation exposure. The United States and United Kingdom use PC as specific criteria for decisions on the compensability of workers’ radiation-related health effects. In Korea, PC was developed firstly as Korean Radiation Risk and Assigned Share (KORRAS) in 1999. In 2015, the Occupational Safety and Health Research Institute and Radiation Health Research Institute jointly developed a more revised PC program, Occupational Safety and Health-PC (OSH-PC). Between 2005 and 2015, PC was applied in 16 claims of workers’ compensation for radiation-related cancers. In most of the cases, compensation was given when the PC was more than 50%. However, in one case, lower than 50% PC was accepted considering the possibility of underestimation of the cumulative exposure dose.ConclusionsPC is one of the most advanced tools for estimating the causation of occupational cancer. PC has been adjusted for baseline cancer incidence in Korean workers, and for uncertainties using a statistical method. Because the fundamental reason for under- or over-estimation is probably inaccurate dose reconstruction, a proper guideline is necessary.

Health effects 20 years after the Chernobyl accident

The Chernobyl accident was the worst catastrophe involving radiation to humans. Since then, it has unfortunately been providing a main cause of radio-anxiety. WHO suggested 4000 people could have died or could die in the future of emergency workers and residents of most contaminated areas while Greenpeace insisted that there would be 93,080 people in the world. Though the incidence of thyroid cancer increased at the Chernobyl area, it is not accepted by the experts because the area that was less contaminated by radiation has a greater reported incidence of thyroid cancer. So, it might be due to a screening effect. There is no convincing evidence that the incidence of leukaemia and solid cancer has been increased in the exposed populations, but it remains a controversial issue. Additionally, the apparent evidence of decreased fertility and increased hereditary effects was not observed in the general population.